Cisapride partially rescued cell surface expression of the L1825P mutant channel, increasing late sodium current from 1.2+/-0.11 to 5.04+/-0.77 pA/pF (P<0.05) and exaggerating the LQT3 phenotype.
Does cisapride rescue cell surface expression of the L1825P mutant SCN5A channel in transfected CHO cells?
Cisapride may cause torsade de pointes not only by blocking IKr but also by rescuing cell surface expression of the L1825P mutant sodium channel, revealing a novel mechanism for drug-induced long-QT syndrome.
p-value: p=<0.05
BACKGROUND: The cardiac sodium channel (SCN5A) mutation L1825P has been identified in a patient with drug-induced torsade de pointes precipitated by the IKr blocker cisapride. Although L1825P generates late sodium current typical of SCN5A-linked long-QT syndrome (LQT3) in vitro, the patient reported had a normal QT interval before administration of the drug. To address this discrepancy, we tested the hypothesis that this mutant channel is not processed normally. METHODS AND RESULTS: CHO cells transfected with L1825P displayed significantly reduced peak INa (209+/-36 versus 23+/-3 pA/pF, P<0.05). Confocal imaging and cell-counting studies using epitope-tagged constructs demonstrated that cell surface expression of the mutant was only approximately 9% of wild-type. Incubating transfected cells with cisapride partially rescued misprocessing to 30% of wild-type. As a result, "late" sodium current increased with cisapride from 1.2+/-0.11 to 5.04+/-0.77 pA/pF (P<0.05). CONCLUSIONS: L1825P fails to generate QT prolongation because it does not reach the cell surface. Moreover, the data suggest that cisapride caused torsade de pointes not only by blocking IKr but also by rescuing cell surface expression of the mutant channel, further exaggerating the LQT3 phenotype. This not only represents a new mechanism in the drug-induced long-QT syndrome but also strongly supports the concept that variable cell surface expression contributes to clinical variability in the LQT3 phenotype.
Liu et al. (Mon,) conducted a other in Drug-induced torsade de pointes / LQT3. Cisapride vs. Wild-type or untreated cells was evaluated on Peak INa, cell surface expression, and late sodium current (p=<0.05). Cisapride partially rescued cell surface expression of the L1825P mutant channel, increasing late sodium current from 1.2+/-0.11 to 5.04+/-0.77 pA/pF (P<0.05) and exaggerating the LQT3 phenotype.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: